UK-CTAP meeting, 10 March 2021.
Held via video teleconference.
Some information has been redacted for the reasons listed in ‘details’ for UK COVID-19 Therapeutics Advisory Panel: records of decisions.
1. Welcome and introductions
Chair welcomed the group and asked members if any new conflicts of interest had arisen.
Declarations
Frederick Hayden declared Science Advisory Board member COVID-19 Early Treatment Fund.
Action
Will recuse for any decisions regarding fluvoxamine.
No other conflicts were recorded.
The record of decisions from the last meeting (10 February 2021) were agreed without amendment.
2. Confirmation of agreement by email
Chair confirmed the recommendations made out of committee.
The recommendation of infliximab in preference to adalumimab into the RECOVERY trial.
3. Drugs discussed and decisions
3.1 Selective serotonin reuptake inhibitor (SSRIs) and serotonin-norepinephrine reuptake inhibitor (SNRIs)
Charlotte Summers and Duncan Richards did not make decisions regarding HEAL inclusion as co-investigators.
Chair introduced the SSRI class of drugs noting they were widely understood and widely used as an antidepressant. The rationale for use was an anti-inflammatory and antiviral effect.
Chair highlighted a US in vivo study using standard human dosing. The safety profile showed links to long QT, an anti-coagulation effect inhibiting platelet aggregation, and negative drug drug interaction with anticoagulants.
The panel noted that the antiviral effect seen in in- vitro trials was not convincingly demonstrated in in- vivo.
It further noted that the anti-inflammatory effect sought was most likely to be delivered by fluvoxamine, and inflammatory changes in the brain parenchyma have also been associated with depression.
The panel agreed that the degree of effect was questionable and that it was not the step change sought in RECOVERY and may be better placed in PRINCIPLE.
A suggestion was made that the dual mode of action, antidepressant and anti-inflammatory, could make it a candidate for HEAL, but it was noted that depression was not a focus of the HEAL platform.
Recommendation
The panel agreed to await the outcome of existing phase 3 trials (due quarter three 2021) of fluvoxamine before reconsidering.
The following SSRIs and SNRIs were not currently recommended:
- citalopram
- [redacted for commercial sensitivity]
- escitalopram
- fluoxetine
- paroxetine
- sertraline
- [redacted for commercial sensitivity].
4. Subgroup advice
4.1 Prophylaxis subgroup
Chair noted that update was for information only as the recommendation to trial was in the gift of the Prophylaxis Oversight Group (POG).
Subgroup chair noted that there was one recommendation going forward to the POG for iota-carrageenan. This product was a non-medicinal physical barrier, for the nasal epithelium.
Discussion in the subgroup had focused on the plausibility of the nasal epithelium as the primary site of infection, and the plausibility was agreed. However, protecting the nose would not be expected to prevent infection acquired at other sites in the respiratory tract.
The group agreed that there was a consistent, if not large, signal of efficacy in other respiratory virus infections that may have small effect on a large number in COVID-19.
Subgroup chair fed back on discussion about antiviral treatment driving resistance, as asked at the UK-CTAP of 11 February 2021.
The panel heard that it was plausible that the antiviral resistance seen in HIV and flu, could be driven by the use of single low potency antivirals. This posed a risk of driving antiviral resistance not only in COVID-19 but other diseases.
Subgroup chair noted that to date the focus had been pre-exposure prophylaxis and that consideration should be given to post-exposure prophylaxis in settings including, non-COVID hospitalised patients, families and student cohorts.
Recommendation
The group agreed that the risk of low potency antivirals driving resistance should inform future discussion and decisions.
4.2 Immune subgroup
Subgroup chair presented the advice of the auto-immune subgroup.
Sphingosine modulators
These are used in the treatment of multiple sclerosis. The group agreed there was not sufficient evidence for inclusion in any of the platform trials.
Opaganib
The panel heard this sphingosine kinase inhibitor was of interest to the subgroup, and further information was requested to consider the outcome of current phase 2 trials.
Metformin
The panel heard advice from the subgroup that this was widely used, well understood compound with a good safety profile in the treatment of diabetes.
The subgroup advised it should be considered for the HEAL platform because of its effect on interstitial fibrosis and the effect on AMP kinase improving respiratory muscle performance.
The panel noted that the other therapeutics subgroup had reviewed a rapid brief on [redacted for commercial sensitivity] inhibitor and recommended further due diligence work should be done to review Metformin and [redacted for commercial sensitivity] inhibitor in comparison.
The panel considered subgroup advice of 25 February 2021.
Recommendation
The panel agreed opaganib was of interest and the UK-CTAP secretariat should obtain more information on the identified phase 2 trial readout.
The panel agreed that metformin was interesting in the context of the HEAL platform trial, but that it should be considered alongside [redacted for commercial sensitivity] inhibitor which was considered by the other therapeutics’ subgroup.
The panel agreed the following drugs are not currently prioritised [redacted for commercial sensitivity].
4.3 Other therapeutics subgroup
Subgroup chair introduced the considerations of three antifibrotics.
[Redacted for commercial sensitivity]
The panel heard advice that there was limited evidence on lung-fibrosis in COVID-19 and post-hospital discharge COVID-19. Although, preliminary clinical observations report reduced lung function and lung fibrosis in post-hospitalised COVID-19 patients with or without ICU admission.
Preliminary clinical observations also suggest that current anti-inflammatory treatments like dexamethasone or tocilizumab are not sufficient to prevent post discharge sequelae.
The panel agreed there was interest to study the antifibrotics [redacted for commercial sensitivity], with clear patient stratification given the safety profile in order to target therapy to those most at risk but noted that currently no validated biomarkers predictive of fibrosis were available in COVID-19 patients.
The panel considered pamrevlumab was too early in clinical development to be considered.
The panel noted the subgroups preference to intervene early to prevent the development of fibrosis or its progression, but the timing of intervention is unclear and would likely require collaboration between REMAP CAP and HEAL.
The panel noted the PHOSP study readout would be helpful to understand pathological changes post-discharge and to assess the clinical utility of anti-fibrotics.
The panel heard advice that [redacted for commercial sensitivity] inhibitor was a drug of interest due to its cardiovascular effect
The panel heard evidence gathered from vitamin D experts on the unlikely efficacy of vitamin D in an acute setting.
Experts agreed that there was evidence that deficiency equated to negative outcomes, but there was little evidence to suggest supplementation or high-dose intervention equated to positive outcomes.
The panel noted that very high doses carried a risk of harm to bone health.
The subgroup chair highlighted a Brazilian high dose vitamin D study that had shown no benefit. Also noted was the withdrawal, from the Lancet, of a pre-print of a Spanish study that claimed high impact for a modest dose.
The panel noted the group had also considered:
- acetazolamide
- [redacted for commercial sensitivity]
- clonidine
- ozone therapy.
Recommendation
The panel agreed [redacted for commercial sensitivity] were plausible treatments for patients with prolonged periods in ICU with evidence of lung fibrosis, or in COVID-19 patients post hospital discharge with evidence of lung fibrosis. Further work on stratification was required before a full recommendation could be made.
The panel reaffirmed its position that low vitamin D level was a risk factor in a number of illnesses but there was no rationale for an interventional trial in the platforms to which it could recommend, and that a large-scale health care study of moderate at-risk populations was more appropriate.
The panel agreed the following treatments are not currently prioritised:
- [redacted for commercial sensitivity]
- clonidine
- ozone therapy.
Action
UK-CTAP secretariat to develop a full brief on [redacted for commercial sensitivity] for the other therapeutics subgroup review alongside metformin, with the support of an expert diabetologist.
4.4 Antiviral subgroup
The panel heard advice on dihydroorotate dehydrogenase (DHODH) inhibitors a class of antiviral compounds, several of which are in clinical trials
The panel noted delay in reaching steady state found in some members of class and expressed concern around the possibility of myelotoxicity.
It was noted that each compound has specific efficacy, dosage, and safety issues to consider [redacted for commercial sensitivity].
The panel heard amantadine showed no evidence of a selective anti-SARS-CoV2 mechanism in vitro and that there was no in vivo data with only anecdotal data available for use in COVID-19
The panel heard [redacted for commercial sensitivity] showed no clear antiviral mechanism or evidence of efficacy inhibiting SARS-CoV2, and the subgroup would be interested in vivo animal model or clinical evidence for COVID-19
The panel noted that the daclatasvir was reviewed again in the light of the completion of large Iranian clinical trial six weeks ago. The subgroup awaits the full clinical trial readout
The panel noted the subgroups consideration of neutralising antibodies: hyperimmune globulin and monoclonal antibodies (mABs)
The panel noted concerns expressed around the potential variability of convalescent plasma, whereas hyperimmune globulin is standardised and cost effective
Hyperimmune globulin provides option to capture recent infections with variants, and that IM formulation of hyperimmune globulin would permit outpatient trials
The panel noted the subgroup preferred mABs due to safety, consistency and specificity but variants arising require combinations which added complexity and cost. With numerous mABs in trials, it is unclear what mechanism for defining cocktail mix
The panel heard that NHS Blood and Transplant have stopped harvesting convalescent plasma.
Recommendation
DHODH inhibitors are not currently prioritised for trial.
Amantadine is not currently recommended for any platform.
Action
The antiviral subgroup will review the readout from LifeArc DEFEAT-COVID and IONIC on leflunomide and IMU-838, respectively.
UK-CTAP secretariat expand report on [redacted for commercial sensitivity] PK, toxicity and safety in AML trials for phase 2a potential.
UK-CTAP secretariat expand report on [redacted for commercial sensitivity] toxicity and safety for phase 2a potential.
[Redacted for commercial sensitivity]
Antiviral subgroup to re-review daclatasvir when the full clinical trial readout of Iranian trial is published.
5. Any other business
Principal investigator’s (PI) view of the trial landscape
Chair invited trial platform PIs to outline their view of the trial landscape.
The panel noted that trials were seeing declining patient numbers, but that opportunities for international arms were increasing although the costs and availability of drugs would preclude some trial arms opening internationally.
The panel heard that declining patient numbers offered an opportunity to assess therapeutics that would be valuable in the event of a third wave of COVID in the UK.
6. Close
Chair thanked the group and closed the meeting.
Attendees
Scientific experts
- Patrick Chinnery (Chair)
- Michael Jacobs
- Frederick Hayden
- Charlotte Summers
- Duncan Richards
- Munir Pirmohamed
Observers
- 5 trial investigators
- 1 Department of Health and Social Care representative
- 7 secretariat members
Apologies
- Ian Hall
- Moira Whyte